Effect of hormones: What a headache specialist needs to know

Migraine has long been thought to be more common in boys prior to age 12, and in girls and women after that. Other studies have not shown a difference between boys and girls prior to puberty, or even that girls still have a higher prevalence of migraine than boys prior to puberty. Regardless, prevalence of migraine in women rises sharply at puberty. The increase at puberty is thought to be due to the influence of female sex hormones on migraine. Estrogen is thought to be excitatory, progesterone inhibitory. Cyclic fluctuations in these hormones can contribute to migraine. Estrogen reduces the threshold for cortical spreading depression, the putative mechanism for migraine with aura, whereas testosterone increases the threshold for cortical spreading depression.

That estrogen is excitatory and reduces the threshold for cortical spreading depression is fascinating, since many women have pure menstrual migraine or menstrually-related migraine. The International Classification of Headache Disorders Edition Three (ICHD-3), defines both pure menstrual migraine and menstrually-related migraine in its appendix. Pure menstrual migraine is defined as migraine attacks occurring on day − 2 to + 3 of the menstrual cycle in two out of three cycles, and at no other time during the menstrual cycle. Menstrually-related migraine’s definition is similar, with the additional allowance of having migraine attacks outside of menses. Prior to menses, estrogen decreases . These declining levels of estrogen correlate with increasing migraine attack frequency. Therefore, it is thought that estrogen withdrawal could play a role in pure menstrual migraine and menstrually-related migraine. Accordingly, 70% women using combined oral contraceptives (COCs) reported headaches during the hormone-free “placebo” period at menses in one study.

COCs have long been studied in relationship to migraine. A recent systematic review by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH) found that there is low quality evidence for any hormonal interventions in migraine. Desogestrel 75 μg/day was shown to improve migraine in women with both migraine with and without aura, but not necessarily related to menstruation. Studies were limited to women taking this medication for gynecologic (medical or for contraception) reasons and not specifically for migraine. In some women desogestrel actually worsened migraine, and has been found to have an unfavorable side effect profile (bleeding). Extended COC use without placebo hormone-free intervals has been studied in the observational setting and may improve migraine outcomes in women. Only one study looked at strictly migraine patients and only one (a different study) study looked at comparison between traditional 21 day on and 7 day off COC and extended COC use without hormone-free interval. All studies, again, evaluated patients using COCs for gynecologic reasons, not strictly for migraine. Finally, estradiol gel has limited evidence for benefit in menstrual migraine, however the challenge of dosing and timing remains elusive. This was recommended for women with stable, predictable menstrual cycles and brings the risk of withdrawal headache (delayed headache) after the estrogen gel period stops.

The EHF and ESCRH pointed out in the above systematic review and recommendations statement that COCs were not recommended in patients with migraine with aura. There has been concern for long and many studies about the increased risk of stroke in migraine with aura patients taking COCs. A recent systematic review found limited evidence to support that fear. While there was a relative increase stroke risk demonstrated in migraine with aura patients taking COCs, there was not sufficient data to evaluate if this was a (estrogen) dose-dependent relationship. Interestingly, newer studies did not show as strong of a relationship between stroke risk and COC use in migraine patients as the older studies did. Estrogen dosing now tends to be lower than it was in the past. This is a significant opportunity for further study in this area, as many women with migraine with aura could benefit from COCs for gynecologic reasons, and either they or their physicians (or both) are hesitant to prescribe these medications based on concern for stroke risk. It is important to remember that absolute stroke risk remains low even in migraine with aura patients taking COCs, and as always, a risk/benefit discussion between patient and provider is warranted in case of gynecological need for COCs in these patients.

Hormone fluctuation may also play a role in men. A recent study showed a decrease in testosterone levels and relative increase in estrogen levels in men with migraine compared to controls. Another study showed low levels of testosterone in men with chronic migraine, defined by the ICHD-3 as headaches more than 15 days per month, with at least 8 of those days being migraine. Future research will show if supplementing testosterone can be used as a treatment for migraine in men. Limited previous research has shown a role for supplemental testosterone in both men and women with another primary headache, cluster headache.

With an increasing number of transgender adolescents and young adults taking supplemental hormones for gender reassignment, addressing migraine in this population is important. A Dutch survey of male to female transgender individuals on supplemental estrogen after gender reassignment surgery showed a prevalence of 25%, which is similar to that of women in the general population. Another Italian study showed an increase in headaches in male to female transgender patients on supplemental estrogen, as well as a decrease in female to male patients on supplemental testosterone. Further study in this area may focus on treatment options for transgender individuals on supplemental hormones, as well as, if there is any increased stroke risk with supplemental estrogen in this population.

Non-hormonal treatments are commonly used to treat menstrual migraine. A small double-blind, placebo-controlled study of menstrual migraine patients found that a group given 360 mg of magnesium pyrrolidone carboxylic acid supplemented daily for 2 months had reduced headache days vs. placebo, ⁽ Naproxen 550 mg twice daily from day − 7 to day + 6 of the menstrual cycle showed reduction of headache days, as well as migraine intensity and duration in menstrual migraine patients. Triptans have also been extensively studied in menstrual migraine. There were two positive trials for frovatriptan 2.5 mg once or twice daily from day − 2 to day + 4, . There was one positive trial for naratriptan 1 mg twice daily for five days starting day − 2 to day + 3. Finally, there was one positive trial for zolmitriptan 2.5 mg twice daily or three times daily from day-2 to day + 5. Frovatriptan, naratriptan, and zolmitriptan are three of the longest-acting triptans, so it makes sense why they would be used as prophylaxis in this setting.

A headache specialist should be prepared to ask and receive questions about pure menstrual migraine and menstrually-related migraine management, stroke risk in patients with migraine with aura taking COCs, and hormonal supplementation and migraine. In the years to come, expect further research on these topics as there is a paucity of data, particularly regarding COC estrogen dose and stroke risk and hormonal treatment of menstrual migraine.

The relationship between migraine and hormones: Information to help children and families

Migraine is very common in children and teenagers with about 1 in 10 children and slightly more teenagers suffering from recurrent migraine attacks. Migraine attacks are severe headaches usually occurring in families that often times start to first occur in girls around time of menarche. Monthly hormonal changes are thought to be associated sometimes with onset of migraine especially during the menstrual period. If hormonal changes are affecting headaches, it is important for girls and their families to keep headache diaries to track their monthly headaches and how it relates to their menstrual cycle. Some research has suggested that teen girls with menstrually related migraine had a monthly pattern to their headaches even before their first period. In particular, changes in the hormone estrogen are thought to be most likely to be associated with migraine. This relationship tends to persist going forward into adult years, with migraine about three times more common in adult women than men.

Keeping diaries or journals of headaches is important to keep track of hormonal effects. Good lifestyle practices are important to follow in general, and getting enough exercise and good nutrition and maintaining healthy weight are the first line in management of these headaches. Studies suggest that being significantly overweight can worsen migraine frequency and severity, losing weight can lessen the number of headaches.

When migraine attacks appear to be significantly hormone related, various options for treatment exists in addition to the frequently prescribed medications to take at the onset of a migraine or prevent headaches. Combination oral contraceptives or birth control pills are often prescribed in teenage girls for many reasons, besides for birth control. They can be used to treat acne and also irregular/heavy menstrual periods. Research studies in adult women have shown that combination oral contraceptives containing the hormones estrogen and progesterone can sometimes improve migraine headache frequency, however, sometimes, they can worsen migraine in some. When taking birth control pills with estrogen, most of the migraine attacks tend to happen during the placebo or pill-free week after taking 21 days of active hormone pills. This is probably related to estrogen levels dropping at that time. Omitting the pill free week and going ahead to the next 3 weeks of active hormone present pills can block some of these hormonally related migraine attacks.

In girls with migraine with aura, accompanied by visual changes or numbness in their extremities before the headache, combination oral contraceptives are contraindicated and should be used with caution. There may be some increased risk of stroke in these girls using this combination contraceptive therapy with estrogen and progesterone, although there may be mitigating factors. Other lifestyle issues or medical problems such as cigarette smoking or high blood pressure can increase risk of stroke in teen girls with migraine who are taking this type of birth control pill. Combination oral contraceptives can be used safely in most teen girls with migraine without aura. In some teenagers aura symptoms can start when first using combination birth control pills due to the higher estrogen levels. It is important to discuss with your health care provider, if migraine attacks change their pattern. It is known that pregnancy carries a much higher risk of stroke complications than taking birth control pills. Other alternative forms of contraception should be discussed if increased stroke risk is present, such as migraine with aura, cigarette smoking, high blood pressure or other genetic factors that may be present.